EP0007615B1 - Verfahren zur Herstellung von Aminosäuren und Estern - Google Patents

Verfahren zur Herstellung von Aminosäuren und Estern Download PDF

Info

Publication number
EP0007615B1
EP0007615B1 EP79102617A EP79102617A EP0007615B1 EP 0007615 B1 EP0007615 B1 EP 0007615B1 EP 79102617 A EP79102617 A EP 79102617A EP 79102617 A EP79102617 A EP 79102617A EP 0007615 B1 EP0007615 B1 EP 0007615B1
Authority
EP
European Patent Office
Prior art keywords
alkyl
methyl ester
formula
phenyl
procedure
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired
Application number
EP79102617A
Other languages
English (en)
French (fr)
Other versions
EP0007615A2 (de
EP0007615A3 (en
Inventor
Arthur Allan Patchett
William John Greenlee
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck and Co Inc
Original Assignee
Merck and Co Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Merck and Co Inc filed Critical Merck and Co Inc
Priority to AT79102617T priority Critical patent/ATE1189T1/de
Publication of EP0007615A2 publication Critical patent/EP0007615A2/de
Publication of EP0007615A3 publication Critical patent/EP0007615A3/xx
Application granted granted Critical
Publication of EP0007615B1 publication Critical patent/EP0007615B1/de
Expired legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/20—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals substituted additionally by nitrogen atoms, e.g. tryptophane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring

Definitions

  • the present invention is concerned with an efficient process for preparing a-vinyl substituent-a-amino acids and esters and certain intermediates.
  • a-vinyl-a-amino acids can be prepared by reducing the corresponding ⁇ -ethynyl ⁇ -amino acid. Such processes are described in Tetrahedron Lett. 2745-2748; 3689-3692 (1977).
  • J.C.S. Chem Communication No. 4 (1977), 125 discloses compounds of formula (2) similar to the N-benzylididne-2-amino crotonic acid esters which are used as starting compounds in the process of the invention.
  • An embodiment of the present invention is a process for preparing compounds having the formula: which comprises (a) treating a compound of the formula: with a strong amine base, (b) reacting the product from (a) with an alkylating agent, R 3 X, or and (c) hydrolyzing the product from (b), wherein R is alkyl, alkenyl or substituted alkyl, R 1 is H or lower alkyl, R 2 is the residue of an aldehyde of the formula R 2 CHO having no a-hydrogen, where R 2 is a phenyl or substituted phenyl group wherein the substituents are halo (Cl, Br or I), C 1-3 alkyl or NO 2 , R 3 is alkyl, alkenyl or substituted alkyl, R 4 is alkyl- substituted alkyl- or aryl-sulfonyl, R 5 is alkyl, aryl or alkaryl and X is Cl, Br or I.
  • R is an alkyl, substituted alkyl or alkenyl group.
  • Preferred R substituents are selected from the group consisting of: Especially preferred R groups are or
  • R' is preferably a lower C 1 ⁇ C 3 , alkyl group, such as octyl, hexyl, pentyl, isopropyl, ethyl or methyl.
  • Preferred R 1 groups are C 1 ⁇ C 6 alkyl.
  • a most preferred R 1 group is methyl.
  • R 2 is the residue of an aldehyde of formula R 2 CHO, having no a-hydrogen, where R 2 is a phenyl or substituted phenyl group wherein the substituents are halo (Cl, Br or I) C 1 ⁇ C 3 alkyl or NO 2 .
  • R 2 groups are phenyl, p-chlorophenyl, 4-nitrophenyl and 4-isopropylphenyl.
  • a preferred R 2 group is phenyl.
  • R 3 is an alkyl, alkenyl or substituted alkyl group which is the same as or readily convertible to the R group.
  • Readily convertible R 3 groups are R groups which bear OH groups and are protected. Examples of such protected moieties are and Z is H, lower alkyl e.g. CH 3 or butyl, phenyl or substituted phenyl e.g. p-CH 3- phenyl.
  • a preferred Z group is phenyl.
  • R 4 is an alkyl, substituted alkyl or aryl sulfonyl group such as p-toluenesulfonyl, benzenesulfonyl, nitrophenylsulfonyl, chlorophenylsulfonyl and hexylsulfonyl.
  • X is halo e.g. Br, Cl or I. Chloro is preferred.
  • R 5 is a C,-C s alkyl group e.g. CH 3 , pentyl or isopropyl; an aryl group such as phenyl, bromophenyl, p-totyl and xylyl; an aralkyl group such as benzyl.
  • a preferred R 5 group is the C,-C 5 alkyl moiety, especially methyl.
  • the Schiff base (a) is conveniently prepared from A-chloro-a-amino butyric methyl ester hydrochloride using the process described in Helv. Chem Acta 40, 1531 (1957).
  • the strong base in Step A may be a suitable lithium dialkylamide.
  • bases are lithium diisopropylamide, lithium dimethylamide and lithium dicyclohexylamide and lithium hexamethyldisilazide.
  • a preferred base is lithium hexamethyldisilazide.
  • the liquid reaction medium used for step A is preferably an aprotic medium such as hexamethyl- phospharamide (HMPA)m tetrahydrofuran (THF), ethyl ether and 1,4-dioxane.
  • HMPA hexamethyl- phospharamide
  • THF tetrahydrofuran
  • ethyl ether 1,4-dioxane.
  • a preferred medium is HMPA and THF.
  • Step A is carried out at temperatures ranging from about -70°C to about room temperature.
  • step B is carried out directly on the step A reaction product.
  • step B the (b) compound is treated with an appropriate alkylating agent as defined above.
  • the alkylating agent is added directly to the reaction product (b) in said liquid reaction medium.
  • Step B is carried out at temperatures ranging from about 70°C to room temperature.
  • the ester (d) is then hydrolyzed using a suitable inorganic acid to produce the final product (e) as the acid salt.
  • the hydrolysis step also serves to remove any other blocking groups, e.g., the hydroxyl blocking group present in the R 3 moiety.
  • the final product (e) may be converted to the free base by conventional neutralization.
  • a preferred intermediate used in the inventive process has the formula:
  • the Formula I products have pharmaceutical activity, e.g., as enzyme inhibitors, antihypertensive agents, antitumor agents and antiallergics.
  • a solution of lithium hexamethyldisilazide was prepared by adding 5.5 mmol of butyllithium (2.2 M solution in hexane) to a cooled (-70°C) solution of 1.15 ml of hexamethyldisilazane in 12.5 ml of tetrahydrofuran. To this solution was added first 3.5 ml of hexamethylphosphoramide and then a solution of 1.15 g of N-benzylidine-2-aminocrotonic acid methyl ester in 12.5 ml of tetrahydrofuran.
  • Example 1B alkylation was carried out with N-benzylidine-3-amino-1-bromopropane.
  • the crude product was mixed with 100 ml. of 6N hydrochloric acid and the well-stirred mixture was heated at 110°C. for 2 hours.
  • the solution was cooled, extracted four times with 10 ml. of methylene chloride, and treated with activated charcoal.
  • the solution was filtered and evaporated, and the residue purified on DOWEX 50W-X4 cation exchange resin, eluted first with water and then with 2N hydrochloric acid, giving 0.560 g.
  • DOWEX 50W-X4 cation exchange resin elution with water and then 2N aqueous hydrochloric acid

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Indole Compounds (AREA)

Claims (7)

1. Verfahren zur Herstellung von Verbindungen der Formel:
Figure imgb0047
dadurch gekennzeichnet, daß man
(a) eine Verbindung der Formel:
Figure imgb0048
mit einer starken Aminbase behandelt,
(b) das Produkt aus (a) mit einer Verbindung der Formel R3X,
Figure imgb0049
Figure imgb0050
oder
Figure imgb0051
umsetzt und
(c) das gemäß (b) erhaltene Produkt hydrolysiert, worin R Alkyl, Alkenyl oder substituiertes Alkyl ist, R1 H oder Niederalkyl ist, R2 der Rest eines Aldehyds der Formel R2CHO, der keinen α-Wasserstoff aufweist, ist, worin R2 eine Phenyl- oder substituierte Phenylgruppe ist, in der die Substituenten Halogen (CI, Br oder J), C1-3Alkyl oder NO2 sind, R3 Alkyl, Alkenyl oder substituiertes Alkyl ist, R4 Alkyl-, substituiertes Alkyl- oder Aryl-sulfonyl ist, R5 Alkyl, Aryl oder Alkaryl ist und X Cl, Br oder J ist.
2. Verfahren nach Anspruch 1, dadurch gekennzeichnet, daß die Aminbase Lithiumhexamethyldisilazid ist.
3. Verfahren nach Anspruch 2, dadurch gekennzeichnet, daß R2 Phenyl ist.
4. Verfahren nach Anspruch 3, dadurch gekennzeichnet, daß der unter (b) angegebene Reaktionsteilnehmer R3X ist.
5. Verfahren nach Anspruch 4, dadurch gekennzeichnet, daß R3
Figure imgb0052
Figure imgb0053
Figure imgb0054
Figure imgb0055
ist, worin Ph Phenyl ist.
6. Verfahren nach Anspruch 5, dadurch gekennzeichnet, daß R3
Figure imgb0056
Figure imgb0057
oder
Figure imgb0058
ist.
7. Verfahren nach Anspruch 3, dadurch gekennzeichnet, daß der unter (b) angegebene Reaktionsteilnehmer
Figure imgb0059
ist.
EP79102617A 1978-07-24 1979-07-24 Verfahren zur Herstellung von Aminosäuren und Estern Expired EP0007615B1 (de)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AT79102617T ATE1189T1 (de) 1978-07-24 1979-07-24 Verfahren zur herstellung von aminosaeuren und estern.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US92720978A 1978-07-24 1978-07-24
US927209 2001-08-10

Publications (3)

Publication Number Publication Date
EP0007615A2 EP0007615A2 (de) 1980-02-06
EP0007615A3 EP0007615A3 (en) 1980-05-28
EP0007615B1 true EP0007615B1 (de) 1982-06-16

Family

ID=25454396

Family Applications (1)

Application Number Title Priority Date Filing Date
EP79102617A Expired EP0007615B1 (de) 1978-07-24 1979-07-24 Verfahren zur Herstellung von Aminosäuren und Estern

Country Status (5)

Country Link
EP (1) EP0007615B1 (de)
JP (1) JPS5519281A (de)
AT (1) ATE1189T1 (de)
DE (1) DE2963107D1 (de)
DK (1) DK309379A (de)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5245046A (en) * 1988-11-14 1993-09-14 The Upjohn Company α-amino-indole-3-acetic acids useful as anti-diabetic, anti-obesity and anti-atherosclerotic agents
JPH06507402A (ja) * 1991-03-20 1994-08-25 ワーナー−ランバート・コンパニー 治療活性を有するα−置換ポリペプチド

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4401676A (en) * 1977-06-01 1983-08-30 Merck & Co., Inc. Novel α-amino acids
GB2001627B (en) * 1977-07-01 1982-04-28 Merrell Toraude & Co Alpha-vinyl and acetylene amino acid derivatives
US4103089A (en) * 1977-07-01 1978-07-25 Merrell Toraude Et Compagnie α-Acetylene and α-vinyl derivatives of amino acids
CA1157030A (en) * 1977-07-01 1983-11-15 Brian W. Metcalf .alpha.-VINYL AMINO ACIDS

Also Published As

Publication number Publication date
EP0007615A2 (de) 1980-02-06
JPS5519281A (en) 1980-02-09
ATE1189T1 (de) 1982-07-15
EP0007615A3 (en) 1980-05-28
DE2963107D1 (en) 1982-08-05
DK309379A (da) 1980-01-25

Similar Documents

Publication Publication Date Title
CZ384697A3 (cs) Způsob přípravy kyseliny (S)-3-(aminomethyl)-5-methylhexanové
DE69616446T2 (de) Verfahren zur herstellung von alpha-haloketonen, alpha-halohydrinen und epoxiden
JPS6055506B2 (ja) 新規ω−アミノカルボン酸アミドとその製法
JPS626718B2 (de)
JP3351563B2 (ja) ３−ヒドロキシ酪酸誘導体の製造法
EP0007615B1 (de) Verfahren zur Herstellung von Aminosäuren und Estern
US4337346A (en) α-Hydroxyaldehyde and a process for preparing the same
US4275220A (en) Process for preparing amino acids and esters
JPS6151578B2 (de)
US4347375A (en) Process for preparing amino acids and esters
US5684161A (en) Process for preparing 1-substituted pyrrole-3-carboxylic acid derivatives
JPH0141142B2 (de)
KR100856133B1 (ko) 아토르바스타틴의 개선된 제조방법
JP2771257B2 (ja) イミダゾール誘導体の製法
JPH04230241A (ja) α−ヒドロキシエステルの合成法
US5142066A (en) Stereoselective process for the preparation of 2-amino-ethanol derivatives having a central analgesic activity and intermidiates thereof
SU1250170A3 (ru) Способ получени дихлоргидрата пирбутерола
EP0035060B1 (de) Verfahren zur Herstellung von Cyclopentenolonen
US5262566A (en) Process for the preparation of optically active a-hydroxycarboxylic acids
EP0008657B1 (de) Alpha-Vinyl-alpha-aminosäuren und deren Ester sowie sie enthaltende pharmazeutische Zusammensetzungen
JPS6317869A (ja) ２−低級アルキル−４−アミノ−５−ホルミルピリミジンの製造法
HU223066B1 (hu) Új eljárás (S)-4-amino-hepta-5,6-dién-sav és intermedierjei előállítására, valamint az intermedierek
US20020151722A1 (en) Production method of beta-amino-alpha-hydroxycarboxylic acid
SU1428751A1 (ru) Способ получени S-алкиловых эфиров 2-алкоксикарбонил-2-арилгликолевых кислот
JP2880203B2 (ja) フラノン誘導体の製法

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

AK Designated contracting states

Designated state(s): AT BE CH DE FR GB IT LU NL SE

PUAL Search report despatched

Free format text: ORIGINAL CODE: 0009013

AK Designated contracting states

Designated state(s): AT BE CH DE FR GB IT LU NL SE

17P Request for examination filed

Effective date: 19801104

ITF It: translation for a ep patent filed

Owner name: SOCIETA' ITALIANA BREVETTI S.P.A.

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Designated state(s): AT BE CH DE FR GB IT LU NL SE

REF Corresponds to:

Ref document number: 1189

Country of ref document: AT

Date of ref document: 19820715

Kind code of ref document: T

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 19820731

REF Corresponds to:

Ref document number: 2963107

Country of ref document: DE

Date of ref document: 19820805

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: LU

Payment date: 19830706

Year of fee payment: 5

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: CH

Payment date: 19840430

Year of fee payment: 6

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FR

Payment date: 19840601

Year of fee payment: 6

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: SE

Payment date: 19840630

Year of fee payment: 6

Ref country code: BE

Payment date: 19840630

Year of fee payment: 6

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: AT

Payment date: 19840712

Year of fee payment: 6

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: NL

Payment date: 19840731

Year of fee payment: 6

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DE

Payment date: 19840830

Year of fee payment: 6

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: AT

Effective date: 19850724

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SE

Effective date: 19850725

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CH

Effective date: 19850731

Ref country code: BE

Effective date: 19850731

BERE Be: lapsed

Owner name: MERCK & CO. INC.

Effective date: 19850731

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: NL

Effective date: 19860201

GBPC Gb: european patent ceased through non-payment of renewal fee
NLV4 Nl: lapsed or anulled due to non-payment of the annual fee
REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: FR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 19860328

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DE

Effective date: 19860402

REG Reference to a national code

Ref country code: FR

Ref legal event code: ST

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GB

Effective date: 19881118

EUG Se: european patent has lapsed

Ref document number: 79102617.2

Effective date: 19860729

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT